Haemophilus influenzae type b is the leading cause of
meningitis
in the United States, resulting in an estimated 8,000-11,000 cases
per
year (1,2). Age-specific incidence rates are highest among
children
less than 1 year of age and decrease steadily thereafter. The
case-fatality ratio is approximately 3%-7%, and neurologic sequelae
are common. In addition, H. influenzae type b causes an estimated
6,000 cases a year of other invasive diseases, including
epiglottitis,
pneumonia, cellulitis, and bacteremia (3).

An experimental vaccine composed of the polysaccharide capsule
of
the organism has been shown to be effective in children over the
age
of 18 months (4). However, the vaccine is poorly immunogenic and
not
protective in children under this age, the group at highest risk of
disease. Work is continuing on development of an efficacious
vaccine
for this age group.
*These recommendations were developed in consultation with James
Chin,
MD, Chief, Infectious Diseases Section, California Department of
Health Services; Vincent A. Fulginiti, MD, Chairman, Committee on
Infectious Diseases, American Academy of Pediatrics; Gregory R.
Istre,
MD, Acting State Epidemiologist, Oklahoma State Department of
Health;
Arnold L. Smith, MD, Chief, Division of Infectious Diseases,
Children's Orthopedic Hospital and Medical Center, Seattle,
Washington; and Joel I. Ward, MD, Director of Medical Epidemiology
and
Assistant Professor of Pediatrics and Medicine, Harbor-UCLA Medical
Center, Torrance, California.

Recent studies have shown an increased risk of disease among
close
contacts of persons with H. influenzae disease, suggesting a need
to
consider chemoprophylaxis for prevention of secondary cases,
pending
development of a satisfactory vaccine.

Risk of secondary disease: Six studies have estimated the risk
of
disease among household contacts of cases in the month following
onset
of disease in the index case (3,5-9). Attack rates varied
substantially with age; the rate was 3.8% among children under 2
years
of age, 1.5% among children 2-3 years of age, 0.1% among children
4-5
years of age, and 0% among contacts over the age of 6 years. The
attack rate for all ages was 0.3%. This represents approximately a
600-fold increase in risk, compared with the risk in the population
at
large. Fifty percent of associated cases occurred within 3 days of
onset in the index case and 75% within 7 days (Figure 2 (3,5-9)).

Whether increased risk of disease occurs in day-care center
contacts of children with invasive H. influenzae disease has not
been
resolved. Numerous clusters of cases in day care-centers have been
reported, but only one study has looked systematically at attack
rates
in day-care center contacts; in that study, 1% (1/91) of day
care-center contacts less than 4 years of age acquired invasive
disease in the month after the index case, compared with 2% (3/131)
of
household contacts less than 4 years of age (9). Carriage rates
among
contacts were only slightly higher in households than in day-care
centers (Figure 3) (9). This study looked only at contacts in the
same
classroom as the index case.

It is not known whether the risk of secondary cases is
different
for persons in contact with a case with meningitis than for those
in
contact with cases with epiglottitis or other invasive H.
influenzae
diseases. Carriage rates among contacts of meningitis patients
have
been reported as lower than carriage rates among contacts of
patients
with other clinical syndromes (9), and secondary cases have been
reported among both groups. At this time, all index cases with
invasive H. influenzae disease are considered to increase the risk
for
contacts.

Efficacy of chemoprophylaxis: Initial studies focused on
usefulness of various antimicrobial agents to eliminate
nasopharyngeal
carriage of H. influenzae type b. Ampicillin,
trimethoprim-sulfamethoxazole, erythromycin-sulfisoxazole, and
cefaclor were shown to eliminate carriage in fewer than 70% of
culture-positive contacts. Also, in persons with H. influenzae
disease, pharyngeal carriage of the organism has been shown to
persist
following intravenous therapy with chloramphenicol or ampicillin.

Rifampin in a dosage of 10 mg/kg per dose* administered twice a
day for 2 days, the regimen currently recommended for meningococcal
chemoprophylaxis, failed to eradicate carriage in as many as 36% of
culture-positive individuals (9,10). However, rifampin in a dosage
of
20 mg/kg per dose* once daily for 4 days (maximum dose 600 mg)
eradicated carriage in 90%-100% of contacts treated (9,11,12).
*Dose is halved for neonates--see below.

A recent multicenter, randomized, placebo-controlled trial
among
both household and day-care center contacts has evaluated the
efficacy
of rifampin chemoprophylaxis in preventing secondary cases of H.
influenzae disease. The study included day-care centers in which
at
least 75% of those present received chemoprophylaxis. Pilot
studies
had demonstrated that, if fewer than 75% participated, rates of new
acquisition of H. influenzae carriage among those receiving either
rifampin or placebo were similar. Four secondary cases occurred
among
the 800 placebo-treated contacts in contrast to no cases among the
1,166 rifampin-treated contacts (p = 0.03). Analysis of attack
rates
among children under 4 years old by place of exposure showed a
trend
toward efficacy in both households (3/131 placebo recipients vs.
0/173
rifampin recipients, p = 0.08) and day-care centers (1/91 placebo
recipients vs. 0/264 rifampin recipients, p = 0.26), but the small
number of secondary cases precluded detailed analysis of subgroups
(9). Anecdotal reports have appeared about the failure of rifampin
to
prevent secondary cases (13).

Implementation of chemoprophylaxis: Mixing rifampin with
applesauce results in peak serum and salivary concentrations that
are
not significantly different from those obtained with a specially
prepared suspension (14). The applesauce mixture is the
formulation
used in the multicenter trial examining the prevention of secondary
cases (9). A suspension of rifampin can also be prepared in United
States Pharmacopeia (USP) syrup.

Side effects of rifampin in the 20 mg/kg dosage occurred in 20%
of
recipients, compared with 11% of placebo recipients. Side effects
included nausea, vomiting, diarrhea, headache, and dizziness. The
rate was similar to the 24% rate of adverse effects in recipients
of
rifampin at a dosage of 10 mg/kg. No serious adverse reactions
occurred (9). Orange discoloration of urine was noted in 84% of
rifampin recipients. Rifampin usage may also cause discoloration
of
soft contact lenses or ineffectiveness of oral contraceptives.

Concern has been raised about the possibility of developing
rifampin-resistant H. influenzae isolates. None of the isolates
from
index patients or contacts was rifampin-resistant in the
multicenter
chemoprophylaxis trial (9), although an occasional
rifampin-resistant
strain has been reported. Monitoring strains causing invasive
disease
for development of rifampin resistance will be important for
assessing
the continued usefulness of rifampin as a chemoprophylactic agent.

Questions have been raised about the difficulties of
coordinating
and implementing chemoprophylaxis in a day-care center. These
concerns are especially relevant in view of the observation noted
previously that chemoprophylaxis is unlikely to be effective if
fewer
than 75% of contacts actually receive rifampin. Several approaches
have been successfully used. The local health department in
Sarasota,
Florida provided rifampin following consultation with private
physicians. The Oklahoma State Health Department distributed a
letter
from the health department to contacts containing information about
the disease and the risk of secondary spread, and recommending that
parents contact their physicians for a rifampin prescription.
State
and local health departments should collaborate with private
practitioners to monitor the completeness and timeliness of
participation in chemoprophylaxis. Studies to document the risk of
secondary cases with and without chemoprophylaxis and to evaluate
the
rifampin sensitivity of isolates causing invasive disease should
also
be considered. As such data become available, appropriate changes
in
these recommendations can be made.

Recommendations: In view of the increased risk of disease in
household contacts less than 4 years of age and the efficacy of
rifampin in eliminating carriage of H. influenzae organisms and
preventing secondary cases of disease, it is recommended that:

Contacts who develop symptoms suggestive of H. influenzae

type b disease, such as fever or headache, should be evaluated
promptly by a physician.

2. In any household in which a case of invasive H. influenzae
disease has occurred and in which another child less than 4 years
of
age resides, all members of the household, including adults, should
receive rifampin in a dosage of 20 mg/kg per dose once daily
(maximum
dose 600 mg/day) for 4 days; dose for neonates ( 1 month) is 10
mg/kg
once daily for 4 days.

3. In day-care center classrooms in which a case of H.
influenzae disease has occurred and in which children less than 4
years of age are present, all parents should be notified
(preferably
in writing) regarding occurrence of a case and the possibility of
increased risk to their children. The symptoms to look for, the
usefulness of rifampin chemoprophylaxis, and the need for prompt
medical evaluation if symptoms occur should be stated. All
students
and staff in the classroom should be considered for
chemoprophylaxis
according to the above regimen. It should be noted, however, that
the
data on risk of secondary spread and efficacy of chemoprophylaxis
in
day-care centers are less complete than for household contacts.

4. Chemoprophylaxis should be instituted as rapidly as
possible
following onset of disease in the index case. If more than 7 days
have passed since the last contact with the index case,
chemoprophylaxis is probably not indicated.

5. The index case should be treated with the same rifampin
regimen before discharge from the hospital.

6. Nasopharyngeal carriage studies should not be employed as
a
guide for chemoprophylaxis because of the lack of correlation of
carriage with risk of disease and because the time required to
complete such studies would delay implementation of
chemoprophylaxis.

7. Rifampin should not be used in pregnant women, because it
is
teratogenic in laboratory animals.
Reported by Respiratory and Special Pathogens Epidemiology Br,
Bacterial Diseases Div, Center for Infectious Diseases, CDC.

References

Fraser DW, Geil CC, Feldman RA. Bacterial meningitis in
Bernalillo County, New Mexico: a comparison with three other
American populations. Am J Epidemiol 1974:100:29-34.

Granoff DM, Basden M. Haemophilus influenzae infections in
Fresno
County, California: a prospective study of the effects of age,
race, and contact with a case on incidence of disease. J
Infect
Dis 1980;141:40-6.

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